Ruthenium-Catalyzed Oxidative Synthesis of N-(2-triazine)indoles by C-H Activation

1,3,5 triazines, especially indole functionalized triazine derivatives, exhibit excellent activities, such as anti-tumor, antibacterial, and anti-inflammatory activities. Traditional methods for the synthesis of N-(2-triazine) indoles suffer from unstable materials and tedious operations. Transition-metal-catalyzed C-C/C-N coupling provides a powerful protocol for the synthesis of indoles by the C-H activation strategy. Here, we report the efficient ruthenium-catalyzed oxidative synthesis of N-(2-triazine) indoles by C-H activation from alkynes and various substituted triazine derivatives in a moderate to good yield, and all of the N-(2-triazine) indoles were characterized by 1H NMR, 13C NMR, and HRMS. This protocol can apply to the gram-scale synthesis of the N-(2-triazine) indole in a moderate yield. Moreover, the reaction is proposed to be performed via a six-membered ruthenacycle (II) intermediate, which suggests that the triazine ring could offer chelation assistance for the formation of N-(2-triazine) indoles.


Introduction
Indoles are one of the most important nitrogen heterocycles in medicinal chemistry, natural products, and organic synthesis [1][2][3][4][5][6][7]. Additionally, indoles are termed privileged motifs because of their excellent biological activities and applications in drug discovery. For these reasons, the construction of indoles has attracted considerable attention over the past few decades [8][9][10][11]. Among these creative approaches, the transition-metalcatalyzed C-H activation strategy of indoles has taken a prominent role. Generally, the activation of the C-H bond of alkylenes requires the participation of transition-metal catalysts [12][13][14][15][16][17] and the assistance of directing groups (amide [18][19][20][21], pyridyl [22,23], pyrimidyl [24], imidazole [25], carboxylic ester [26], and methoxy [27]). In particular, Stuart reported the first example of the synthesis of indoles from N-phenyl-2-aminopyridine and alkyne or alkene via intramolecular oxidative C-N coupling and C-H activation by [Cp*RhCl 2 ] 2 [28]. This powerful protocol provided a new insight for chemists to construct indoles by C-H activation from various substrates or with cheaper catalysts. However, in contrast to rhodium, inexpensive ruthenium or nickel complexes are competent choices for these transformations. Recently, many efficient methods for indole derivatives by the Ru-catalyzed oxidative annulation of 6-anilinopurine or 2-aminopyridine and alkynes have been developed. Nevertheless, innovative approaches to diverse indole derivatives still require further exploration.
On the other hand, triazine is a privileged pharmacophore against various targets, especially indole-substituted triazines, and has been reported to be a potential antibacterial [29], anti-inflammation [30,31] agent and an acetylcholinesterase [32] and cyclic GMP-AMP synthase [33] inhibitor. Normally, unstable cyanuric chloride is used as raw material for the preparation of these compounds through a nucleophilic displacement reaction. Hence, it is significant to develop practical protocols that can meet the demand for sustainable development. More recently, Cui and their group reported the efficient copper-catalyzed  19). We also investigated a set of representative solvents, and DMF was proven to be the best choice for this synthetic methodology (Table 1, entries 20-23). Furthermore, Pd-catalysts were explored as a catalyst system, but the desired product was hardly observed (Table 1, entries 24-25). However, increasing or decreasing the amount of the ruthenium catalyst (10% or 2%) showed less efficiency for the formation of 3a (Table 1, entries 26-27). Based on the previous work [40][41][42][43], we inferred the possible mechanism for ruthenium oxidative annulation approaches. Firstly, cationic ruthenium (II) complex A, which was generated in the presence of Cu(OAc) 2, reacted with 1 to produce B, and six-membered ruthenacycle (II) C was observed through the elimination of AcOH from B [41]. Subsequently, the formation of D was proposed to undergo coordination and migratory insertion with 2 [41,44]. Finally, D underwent reductive elimination to furnish the desired product 3 (Scheme 4). However, replacing the hydrogen atom at C6 of the triazine ring with other groups prevented the formation of vital intermediate B and C. It was clear that no expected corresponding product was observed when there were other groups at C6 of the triazine ring. Then, various alkynes were tested to further investigate the scope of the rutheniumcatalyzed oxidative annulation strategy. Alkynes with electron-donating or withdrawing substituents reacted smoothly with 1a to generate the corresponding products(3m-3p). Furthermore, 1,2-di(thiophen-3-yl)ethyne 1q readily transformed into the desired product 3q at a 45% yield. In order to explore the regioselectivity of the C−H annulation process, unsymmetrically substituted alkyne 1r was performed under optimized conditions. The results showed that 3r and 3r' could be obtained with moderate regioselectivity and a total yield of 55% (Scheme 2). The reaction of 1j (1.00 g) with 2a (1.02 g) under the optimal reaction conditions gave the corresponding product 3j at a 63% yield (Scheme 3). Based on the previous work [40][41][42][43], we inferred the possible mechanism for ruthenium oxidative annulation approaches. Firstly, cationic ruthenium (II) complex A, which was generated in the presence of Cu(OAc)2, reacted with 1 to produce B, and six-membered ruthenacycle (II) C was observed through the elimination of AcOH from B [41]. Subsequently, the formation of D was proposed to undergo coordination and migratory insertion with 2 [41,44]. Finally, D underwent reductive elimination to furnish the desired product 3 (Scheme 4). However, replacing the hydrogen atom at C6 of the triazine ring with other groups prevented the formation of vital intermediate B and C. It was clear that no expected corresponding product was observed when there were other groups at C6 of the triazine ring.

General Information
Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. All reactions were performed in a heating mantle in a sealed tube unless otherwise noted. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and was visualized using UV light. Column chromatography was performed with silica gel (mesh 300-400). 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer in CDCl3 with Me4Si as an internal standard. Data were reported as follows: a chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz) and integration. The HRMS and mass data were recorded by ESI on a TOF mass spectrometer.

General Procedure for the Synthesis of 1
The initial compound 1 was prepared as referred to in our previous work [38,39,45]. Sodium (2.5 eq) was added to anhydrous MeOH at 0 °C until the sodium was completely consumed. Then, biguanides hydrochloride (1.0 eq) was added to the reaction mixture, and 3-4 h later, methyl formate (ethyl acetate for 1l) was added. The above reaction mixture was stirred for another 24 h at 40 °C. When the reaction was complete, the mixture

General Information
Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. All reactions were performed in a heating mantle in a sealed tube unless otherwise noted. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and was visualized using UV light. Column chromatography was performed with silica gel (mesh 300-400). 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer in CDCl 3 with Me 4 Si as an internal standard. Data were reported as follows: a chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz) and integration. The HRMS and mass data were recorded by ESI on a TOF mass spectrometer.

General Procedure for the Synthesis of 1
The initial compound 1 was prepared as referred to in our previous work [38,39,45]. Sodium (2.5 eq) was added to anhydrous MeOH at 0 • C until the sodium was completely consumed. Then, biguanides hydrochloride (1.0 eq) was added to the reaction mixture, and 3-4 h later, methyl formate (ethyl acetate for 1l) was added. The above reaction mixture was stirred for another 24 h at 40 • C. When the reaction was complete, the mixture was concentrated under reduced pressure, and water was added, filtered, washed with water, and dried to produce a crude product. The crude product was purified by recrystallization in MeOH to obtain 1a-1l.
Author Contributions: Reaction optimization and synthesis investigation work were carried out by J.C., F.L. and H.L. Mechanism related work was conducted by D.J. and W.L. NMR and HRMS studies were carried out by J.D. and L.Z. Conceptualisation, supervision, validation, and writing of the manuscript was completed by M.Z. All authors have read and agreed to the published version of the manuscript.